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Current Topics in Peptide & Protein Research   Volumes    Volume 5 
Elevated nuclear Tip60a and NF- κBp65 levels in fragile X syndrome results from altered mRNA binding to FMRP
Natalia Dolzhanskaya, Ying-ju Sung, George Merz, W. Ted Brown, Sarah L. Nolin, Abdeselem El Idrissi, Carl Dobkin, Robert B. Denman
Pages: 201 - 220
Number of pages: 20
Current Topics in Peptide & Protein Research
Volume 5 

Copyright © 2003 Research Trends. All rights reserved


Loss of the RNA binding protein, FMRP results in fragile X syndrome whose clinical presentation includes both mental retardation and dysmorphism. The phenotypic features of the disease may be related to the “mis-metabolism” of the mRNAs that interact with FMRP. We used affinity chromatography coupled to high throughput screening assays to detect brain messenger RNAs (mRNAs) that bind to FMRP in vivo. One of the mRNAs, obtained in a differential display screening of normal human brain mRNA, encoded the human histone acetyltransferase, Tip60a. Tip60a mRNA is abundantly expressed in brain regions that express FRMP, as well as in lymphocytes, where it was initially cloned. Transcription factor NF- κBp65 mRNA was found in a subtractive hybridization screening of embryonic mouse brain mRNAs that interact with FMRP. Secondary affinity capture pull-down assays demonstrated that both messages bind to human FMRP in vitro. Similarly, both messages were detected in the FMRP-immunoprecipitated fraction of cultured cell extracts, implying that they associate with FMRP-containing mRNPs in vivo. We also observed that Tip60a, but not its corresponding mRNA, was elevated 3-fold in fragile X lymphoblastoid cells, suggesting that FMRP negatively regulates its translation. Similarly, NF- κBp65 was elevated from 3-fold in fragile X cell lines but its cytoplasmic, regulatory partner, I- κBα, was not. In addition, significantly more activated NF-κBp65 exists in the nucleus of fragile X lymphoblastoid cells than in normal controls resulting from constitutive activation of an upstream signaling pathway. These data suggest that since Tip60a and NF- κBp65 regulate the expression of a large number of other genes that the fragile X phenotype may arise, in part, by Tip60a- and NF- κBp65- mediated changes in transcriptional activity.

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